Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from the group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired.
On the other hand, a combination therapy is reported to be effective in the treatment for acquired immunodeficiency syndrome because of the frequent emergence of the resistant mutant in Balzarini, J. et al, Proc. Natl. Acad. Sci. USA 1996, 93, p. 13152-13157. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent, however, agents having the same mechanism of action often show the cross-resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.
Examples of the integrase inhibitor include 1,3-dioxobutanoic acids and 1,3-propanediones described in WO99/50245, WO99/62520, WO99/62897, WO99/62513, WO00/39086 and WO01/00578. Anther integrase inhibitor is acrylic acid derivative described in WO01/17968. The other recently reported types are aza- or polyazanaphthalenylcarboamide derivative described in WO2002/30426, WO2002/30930, WO2002/30931 and WO2002/36734.
A compound having a similar structure to the present invention compound is N-substituted-3-carboamide-4-hydroxy-5-oxo-3-pyrroline derivative with an anti-inflammatory effect described in Eur. J. Med. Chemical-Chim. Ther. (1979), 14 (2), 189-190. Pharmazie (1997), 52 (4), 276-278 discloses 1-methyl-4-arylcarbamido-2,3-dioxopyrrolidine derivative as an intermediate. WO92/06954 discloses pyrolizinedione derivative with an inhibitory effect on aldose reductase. J. Med. Chemical (1976), 19 (1), 172-173 discloses N-substituted-4,5-dioxopyrrolidine-3-carboxyanilide derivative with anti-inflammatory effect. Journal of Physical Chemistry A (2002), 106 (11), 2497-2504 discloses pyrimidine derivative without mentioning any pharmaceutical use.
T'ai-wan K'o Hsueh (1997), 31 (3-4), 130-135 discloses 3-hydroxy-7-(phenylmethoxy)-2-(2-quinolinyl)-4H-1-benzopyrane-4-one. Examples of a compound having a structure of “4H-1-benzopyrane-4-one” include flavonoid derivative with anti-HIV activity described in {circle around (1)} J. Nat. Prod. (2001), 64 (4), 546-548, {circle around (2)} Anticancer Res. (2000), 20 (4), 2525-2536, {circle around (3)} WO98/11889, {circle around (4)} Pharmazie (1998), 53 (8), 512-517, though the action of mechanism is not mentioned therein.